controls to minimize disruption of the pharmaceutical

10.5731/pdajpst.2020.012021Access the most recent version at doi: 468-49474, 2020 PDA J Pharm Sci and Tech

T. Cundell, D. Guilfoyle, T. R. Kreil, et al. Chain During the COVID-19 PandemicControls to Minimize Disruption of the Pharmaceutical Supply

on June 11, 2022Downloaded from on June 11, 2022Downloaded from

PDA PAPER

Controls to Minimize Disruption of the PharmaceuticalSupply Chain During the COVID-19 Pandemic

T. CUNDELL1,*, D. GUILFOYLE2, T. R. KREIL3, and A. SAWANT4

1Microbiological Consulting, LLC, Scarsdale, NY; 2Johnson & Johnson, New Brunswick, NJ; 3Takeda, Vienna, Austria;and 4Merck & Co. Inc., Kenilworth, NJ. © PDA, Inc. 2020

ABSTRACT: This article reviews currently available scientific literature related to the epidemiology, infectivity, sur-

vival, and susceptibility to disinfectants of Coronaviruses, in the context of the controls established to meet good manu-

facturing practice (GMP) regulations and guidance, and the public health guidance issued specifically to combat the

COVID-19 pandemic. The possible impact of the COVID-19 pandemic on the pharmaceutical supply chain is assessed

and recommendations are listed for risk mitigation steps to minimize supply disruption to pharmaceutical drug prod-

ucts. Areas addressed include a brief history of the COVID-19 viral pandemic, a description of the virus, the regulatory

response to the pandemic, the screening of employees, the persistence of the virus on inanimate surfaces, cleaning and

disinfection of manufacturing facilities, the use of GMP-mandated personal protective equipment to counter the spread

of the disease, the role of air changes in viral clearance, and approaches to risk assessment and mitigation. Biological

medicinal products have a great record of safety, yet the cell cultures used for production can be susceptible to viruses,

and contamination events have occurred. Studies on SARS-CoV-2 for it ability to replicate in various mammalian cell

lines used for biopharmaceutical manufacturing suggests that the virus poses a low risk and any contamination would

be detected by currently used adventitious virus testing. The consequences of the potential virus exposure of manufac-

turing processes as well as the effectiveness of mitigation efforts are discussed. The pharmaceutical supply chain is

complex, traversing many geographies and companies that range from large multinationals to mid- and small-size oper-

ations. This paper recommends practices that can be adopted by all companies, irrespective of their size, geographic

location, or position in the supply chain.

KEYWORDS: COVID-19 pandemic, SARS-CoV-2 virus, Drug shortage, Supply chain, Employee screening, Risk

assessment, Risk mitigation.

Introduction

During academic training, every microbiologist learns

about pandemics and their impact on society. However,

this bookish knowledge, although foundational, does not

prepare one for all the potential contingencies and scenar-

ios that a pandemic can present. As of the writing this arti-

cle, there is no approved drug to treat COVID-19 infection

and a shortage of testing capabilities to identify the virus in

people exhibiting symptoms of infection and to screen for

viral antibodies to determine infected individuals who

have recovered and might have immunity and return to the

work place. It should be noted that several health author-

ities have given emergency authorization for use of certain

drugs and antibody tests. Further, because of the global

increase in demand and the disruption in transportation,

the COVID-19 pandemic has resulted in major shortage of

medicines needed to treat symptoms of the disease, man-

age pain, or to prevent or control secondary infections. See

the Food and Drug Administration (FDA) Drug Shortage

website for additional information (1). In addition, the pan-

demic has created a shortage of supplies of disinfectants

and sanitizers and personal protective equipment (PPE)

such as masks and gowns needed to meet good manufac-

turing practice (GMP) standards and associated standard

operating procedures (SOPs).

Over the last 20 years, the world has experienced out-

breaks of major novel respiratory infectious diseases

such as the SARS (Severe Acute Respiratory

DISCLAIMER: The following paper is a special contribution from the Parenteral Drug Association (PDA). This article wasreviewed internally by PDA and the task force members and not peer-reviewed by the PDA JPST. Note: This PDA Paper isprotected by copyright and unauthorized distribution or use is prohibited.

* Corresponding Author: Microbiological Consulting,

LLC, Scarsdale, NY. E-mail: [email protected]

The authors are members of the PDA COVID-19 Task

Force.

doi: 10.5731/pdajpst.2020.012021

468 PDA Journal of Pharmaceutical Science and Technology

on June 11, 2022Downloaded from

Syndrome) outbreak (2002), influenza H1N1 pandemic

(2009), and MERS (Middle East Respiratory Syn-

drome) outbreak (2012), and now the COVID-19 pan-

demic (2020). Pandemics can disrupt pharmaceutical

supply in multiple ways at a time when medicines and

vaccines are critically needed to control the pandemic

and treat medical conditions not related to respiratory

illness in other patients. Unavailability of raw materi-

als, manufacturing supplies, shutdown of transportation

systems, and most importantly employee absenteeism

owing to infections, suspected infections, or fear of

infections can disrupt supply. The U.S. FDA published

Guidance for Industry—Planning for the Effects of

High Absenteeism to Ensure Availability of Medically

Necessary Drug Products (2) in March 2011, that is,

following the 2009 Influenza H1N1 pandemic. More

recently, the Medicines and Healthcare products Regu-

latory Agency, United Kingdom (MHRA) (3) and the

World Health Organization (WHO) (4) have published

guidance on flexibilities in response to the COVID-19

pandemic. Since the last pandemic in 2009, there has

been a massive global increase in the use of social

media platforms as a source of information, which may

or may not be accurate and can result in poor decisions

that can impact the drug supply.

This article reviews currently available scientific infor-

mation related to coronaviruses and disinfectants from

peer-reviewed journals, authenticated sources such as

the U.S. federal Centers for Disease Control and Pre-

vention (CDC), FDA, WHO, major health authorities,

and national and international GMP standards. Al-

though the article is primarily directed toward pharma-

ceutical drug manufacturing, the content should be use-

ful to all manufacturers of over-the-counter drug

products, consumer health products, cosmetics, and

medical devices. The question asked is how potential

risks can be identified and mitigated to protect our

manufacturing facilities, employees, drug products,

and customers from this pandemic respiratory virus? It

should be noted that the COVID-19 pandemic is fast

moving, and a tremendous amount of new scientific

knowledge is being created every day. The authors

have endeavored to make recommendations based on

an anticipated progression of the pandemic in general

terms, although the effect of the pandemic locally and

internationally may vary. In addition, local laws, regu-

lations, and other requirements will inform each com-

pany’s specific response to the pandemic.

Potential Risks That Can Result in Drug Shortages

The potential risk associated with COVID-19 can be

categorized into direct risk posed by the virus to

employees and to product and indirect risk to manufac-

turing and distribution activities materialized by policies

and controls promulgated by local, state, and national gov-

ernments to control the pandemic (Figure 1).

To assess the direct risk posed by COVID-19, it is im-

portant to understand the epidemiology, infectivity,

and susceptibility to disinfection.

Epidemiology of the COVID-19 Pandemic and Related

Outbreaks

The 2019 novel coronavirus that was identified as the

cause of an outbreak of respiratory illness is now

referred to as the COVID-19 pandemic with the infec-

tious viral agent designated as SARS-CoV-2. It was

Figure 1

Direct and indirect risks that may result in pharmaceutical drug shortages.

Vol. 74, No. 4, July--August 2020 469


first detected in Wuhan, China, on December 12, 2019

(5) and reported to the WHO China Country Office on

December 31, 2019 (6). By mid-January, COVID-19

spread to Thailand, Japan, and Korea and then to

Europe.

As the rapid spread of SARS-CoV-2 in the U.S.A. is

well documented in the published literature, the authors

have used the U.S. as the basis for discussion. The first

documented U.S. case was a 34-year-old man who

traveled to Wuhan, China to visit family, returned, and

reported to an urgent care clinic in Snohomish County,

Washington on January 19, 2020, in response to a

health alert from the U.S. CDC (7). On March 11,

2020, the WHO declared Coronavirus Disease 2019

(COVID-19) a pandemic (WHO Statement, 2020) as it

had spread to multiple countries with high prevalence

of community transfer. On January 31, 2020, the U.S.

federal Health and Human Service (HHS) issued a dec-

laration of a public health emergency related to

COVID-19 and mobilized the Operating Divisions of

HHS (8). In addition, on March 13, 2020, the President

of the United States declared a national emergency in

response to COVID-19 (9).

By the end of March, there were 240,000 confirmed U.

S. cases with over 7000 deaths, resulting in the declara-

tion of a national emergency by the President of the

United States, with orders for nonessential workers to

work from home. By the end of April, there were over

1 million U.S. confirmed cases and 60,000 deaths.

Pharmaceutical employees involved in production and

testing activities were deemed essential globally;

health authorities issued requests for pharmaceutical

industry to work to avoid drug shortages.

Description of the SARS-CoV-2 Virus

Coronaviruses are lipid-enveloped, single-stranded,

positive sense RNA viruses, with 26 to 32 kilobases,

belonging to the genus Coronavirus, which includes

several relatively benign, seasonal, common cold

viruses and three new, more virulent coronaviruses:

severe acute respiratory syndrome coronavirus (SARS-

CoV), which emerged in the human population in

2003; Middle East Respiratory Syndrome coronavirus

(MERS-CoV), which emerged in humans during 2012;

and SARS-CoV-2 that emerged in late 2019 and

became the COVID-19 pandemic in early 2020

(10–12)

Enveloped viruses like SARS-CoV-2 are highly sus-

ceptible to cleaning agents and disinfectants, above

ambient temperature, and usually do not survive on in-

animate surfaces beyond 2 days. This will be discussed

in more detail in the section on persistence of SARS-

CoV-2. The individual coronavirus particles are around

0.125 lm in diameter. N95 face masks are rated to cap-

ture 95% of particles down to 0.3 lm. This means that

viral particles may still potentially get through this pro-

tection. The virus appears to be dispersed as larger

droplets or aerosols and the multiple layers of the face

masks largely mitigates this risk. In contrast, HEPA fil-

ters are 99.97% effective at 0.3 lm and thus are much

more efficient than face masks.

Sources of the SARS-CoV-2 Virus

Zoonotic respiratory viruses initially emerge by ani-

mal-to-human and then largely by human-to-human

transmission and to a lesser degree surface-to-human

transmission. Dense human populations coexisting

with dense chicken, duck, and pig populations as found

in the People’s Republic of China, as well as the con-

sumption of wild animals as food, favors the emer-

gence of novel respiratory viruses (13, 14). There is

little or no evidence that the coronavirus is either a

foodborne or waterborne viral pathogen.

Foodborne viral pathogens are responsible for a larger

number of illnesses than bacterial pathogens annually.

They may be classified into three main groups of viral

illnesses: viruses that cause gastroenteritis, for exam-

ple, norovirus and rotavirus; enterically transmitted

hepatitis viruses, for example, hepatitis A; and entero-

viruses, for example, poliovirus (15). Notably food-

borne viruses are not associated with respiratory

infection.

According to a March 2020 WHO Interim Guidance

(16), although SARS-CoV-2 persistence in drinking

water is possible, there is evidence from surrogate

human coronaviruses that they are not present in sur-

face or ground water sources or transmitted through

contaminated drinking water. The coronavirus, an

enveloped virus with a fragile outer membrane, does

not survive in the environment and would be suscepti-

ble to filtration and chlorine treatment before water

distribution.

Because SARS-CoV-2 may be shed in fecal matter (up

to 10% confirmed presence in diarrhea) with some



earlier reports of fecal-to-oral transmission (17, 18),

this route of transmission should not be treated casu-

ally, and personnel hygiene should be emphasized in

manufacturing facilities.

Public health experts have ruled out the possibility of

insect-to-human transmission.

Personnel Health and Safety

The biggest risk to the community at large, and as such

to the pharmaceutical supply chain, is human-to-human

transmission of the coronavirus. Protecting the health

and safety of employees should be the top priority of

companies. The following points should be considered

and as appropriate built into the pandemic response

plans developed by individual companies.

Social Distancing and Work from Home

Certain local, state, and national governments and their

health authorities have issued social distancing guide-

lines that may include a mandatory stay at home order

with a caveat to exclude “essential employees,” that is,

employees necessary to keep critical services and

activities in operation. To our knowledge, all govern-

ments combating the pandemic have classified “phar-

maceutical employees” as essential workers. As such,

pharmaceutical companies generally have the liberty to

determine what employees, if any, should work from

home and who should report to work. The authors rec-

ommend companies develop a comprehensive contin-

gency plan to identify essential activities and the

employees needed to execute such activities. Support

staff in quality assurance (QA), regulatory affairs, pur-

chasing, human resources, research and development,

planning, sales and marketing, and general manage-

ment largely may work from home. Staff directly

employed in manufacturing operations, quality control

testing, engineering and maintenance, security, ware-

housing, and shipping must be on site and potentially

expose each other, facilities, and products to viral

contamination.

The employees identified as essential will depend on

the manufacturing sites ability to conduct GMP activ-

ities remotely via a 21 CFR Part 11 compliant informa-

tion technology (IT) system. For example, sites that

have completely electronic batch records may not need

to have a QA batch record reviewer on site, but those

that have paper records or hybrid paper and paperless

systems may need to include such an employee on the

list of essential employees.

Furthermore, the determination of which employees

are considered essential will depend, in part, on the

level of community spread. For example, site auditors

may not be considered essential if the virus threat level

is high within the local community, but as the threat

decreases, auditors may be included in the list of essen-

tial employees.

Employees working off-site, using communication

tools like mobile telephones, e-mail, and videoconfer-

encing, can conduct many support activities in the

pharmaceutical industry. This will significantly reduce

the numbers of employees on-site. In terms of the drug

product supply chain, such employees may be viewed

as nonessential, whereas those employees (operators,

as well as managers) directly involved in product man-

ufacturing, testing, and distribution are viewed as

essential. However, this distinction is not clear-cut. For

example, it may be possible to delay a supplier audit of

a pharmaceutical ingredient used in the manufacture of

an essntail drug product, annual GMP training for

packaging operators, or even marketed product stabil-

ity testing. Determining what are nonessential activ-

ities and what are essential must be approached in a

well-considered manner. The authors recommend that

companies develop pandemic contingency plans that

mandate essential activities and provide justification

and timelines for the completion of activities that are

delayed as nonessential. These plans should be ap-

proved by their quality control unit and may, impor-

tantly, be subject to regulatory review.

Identification of Infected Employees

As we believe that the biggest risk to the supply chain

is person-to-person viral transmission followed by sur-

face-to-person transmission, the most important risk

mitigation will be excluding infected employees, espe-

cially those manufacturing, sampling, and testing drug

products, from the pharmaceutical workplace to main-

tain the workforce and not potentially cause product

contamination.

GMP regulations, for example 21 CFR 211.28 d states:

Any person shown at any time (either by medi-

cal examination or supervisory observation) to

have an apparent illness or open lesions that



may adversely aect the safety or quality of drug

products shall be excluded from direct contact

with components, drug product containers, clo-

sures, in-process materials, and drug products

until the condition is corrected or determined by

competent medical personnel not to jeopardize

the safety or quality of drug products. All per-

sonnel shall be instructed to report to supervi-

sory personnel any health conditions that may

have an adverse eect on drug products.

As such, pharmaceutical companies are required to

have procedures in place and a training program for

employees to self-report and supervisors to observe

and detect illness.

The major symptoms of COVID-19 infection are dry

cough, fever, and difficulty breathing, but asymptom-

atic sufferers may shed the virus (19). All employees

who self-identify as sick must be encouraged to stay

home and report their status to their immediate supervi-

sor and seek medical help. Examples of high-risk fac-

tors include sick family members and friends, recent

foreign and domestic travel, attendance at events with

large crowds such as arena concerts and professional

sport games, frequenting places of worship, schools,

restaurants, social clubs, and bars, dwelling in high-

density population cities and towns, and commuting

using public transportation.

To maximize the possibility that employees will self-

report potential illness, the authors recommend review-

ing sick-leave policies for all employees, including

temporary and contract workers. We also recommend

that companies enhance general awareness about the

symptoms of COVID-19 by reinforcing the need for

self-reporting and supervisory vigilance.

Screening Pharmaceutical Employees at the Point of

Entry to Manufacturing Facilities

Recent epidemiological studies of COVID-19 suggest

that infected individuals may remain asymptomatic or pre-

symptomatic for up to 2weeks (21). Therefore, in addition

to reinforcing GMP requirements to self-report illness,

companies should consider instituting procedures to screen

employees entering manufacturing facilities. Such proce-

dures need to be developed in accordance with govern-

ment-mandated requirements and employee rights to

privacy, avoidance of discrimination, and respect for exist-

ing employee contracts and union agreements.

On April 23, 2020, the U.S. Equal Employment Oppor-

tunity Commission (EEOC) issued an update to its

guidance that now expressly acknowledges that

employers may test employees for COVID-19 and con-

duct temperature-screening measures without violating

the provisions of the Americans with Disabilities Act

(ADA) or the Rehabilitation Act (20). According to the

EEOC, “an employer may choose to administer

COVID-19 testing to employees before they enter the

workplace to determine if they have the virus.” Further,

as stated by the EEOC:

Consistent with the ADA standard, employers

should ensure that the tests are accurate and

reliable. For example, employers may review

guidance from the U.S. Food and Drug Admin-

istration about what may or may not be consid-

ered safe and accurate testing, as well as

guidance from CDC or other public health

authorities, and check for updates. Employers

may wish to consider the incidence of false-pos-

itives or false-negatives associated with a par-

ticular test. Finally, note that accurate testing

only reveals if the virus is currently present; a

negative test does not mean the employee will

not acquire the virus later.

The EEOC guidance applies only with respect to the two

specified federal statutes in the U.S. We recommend that

companies in the U.S. also consider the applicability of rel-

evant state and local law and consult legal counsel as

needed before initiating a mandatory employee-testing pro-

gram. Companies outside the U.S. must obviously consider

applicable national and local laws.

Also, in the U.S., the federal Occupational Safety and

Health Administration (OSHA) recommends that com-

panies develop an Infectious Disease Preparedness and

Response Plan (22). The OSHA updated recommenda-

tions state the following:

If one does not already exist, develop an infec-

tious disease preparedness and response plan

that can help guide protective actions against

COVID-19. Stay abreast of guidance from fed-

eral, state, local, tribal, and/or territorial health

agencies, and consider how to incorporate those

recommendations and resources into work-

place-specific plans. Plans should consider and

address the level(s) of risk associated with vari-

ous worksites and job tasks workers perform at

those sites.



How can employees be screened? Depending on the

nature of the workforce, and the confidence and trust

management has in the workforce, companies should

decide whether to institute mandatory testing and/or

institute self-screening or screening during entrance

into the plant site.

If screening is performed during entrance to your plant

sites, the employees’ entry should be staggered to

maintain social distancing and prevent delays. In addi-

tion to any mandatory COVID-19 testing that may be

adopted, the authors believe in their expert opinion that

the screening may consist of the following activities:

1. Monitor the body temperature of all employees. If

self-monitoring is permitted, employees could check

their body temperature using a personal clinical ther-

mometer just prior to leaving for work. Employees

should not report to work and should seek medical

advice immediately if their body temperature is

above 100.4˚F/38˚C. If screening is conducted at the

plant entrance, a trained screener should use a cali-

brated handheld or wall-attached no-touch thermom-

eter. Employees with a body temperature exceeding

100.4˚F/38˚C should be segregated and not allowed

to enter the facility.

2. Conduct brief interviews of potentially SARS-CoV-

2-infected employees to identify those with the com-

mon symptoms of fever, dry cough, and difficulties

breathing.

3. Take a travel and contact history of a suspected

infected employee for the past 14 days to determine

the potential for contamination of the manufacturing

facility and infection of other employees.

4. Segregate any potentially infected employees and en-

courage them to get medical care through their regu-

lar physician or neighborhood medical center. It

would be useful to provide employees with health-

care contact information.

5. Obtain a commitment from the employee to report

their medical status and results of any testing for the

presence of the coronavirus when they update their

sick leave status according to company policy.

6. Determine whether the infected employee’s co-

workers within social distancing need to be quaran-

tined from the workplace.

7. Determine the potential impact on the manufacturing

operation as a result of employee absences.

8. When an employee is confirmed positive for the co-

ronavirus, clean and disinfect the locations directly

impacted in their workspace and other high-traffic

areas like bathrooms, break rooms, hallways, and

entrances.

9. Review of the frequency of employee exclusions by

a local oversight committee to determine the need for

self-quarantine of potentially infected employees,

institute additional risk mitigations, and determine

the potential impact to the manufacturing schedule.

The recommended screening listed as 1 through 6 will

have recognizable limitations. Multiple screening

methods will most likely be more effective than a sin-

gle method. Clinical thermometers may be in short sup-

ply during a pandemic. Studies on the use of infrared

thermal image scanners in influenza and COVID-19

airport screening (23–25) to identify infected travelers

showed that, compared to virus testing, they might

detect less than half of those infected because of the vi-

ral incubation period and asymptomatic individuals.

Screening each day of entrance to the workplace as

compared to a departure or arrival screening at an air-

port will increase its effectiveness. A recent publica-

tion on the presenting characteristics of 5700 patients

hospitalized with COVID-19 in the New York City

area (26) found that only 31% had an elevated tempera-

ture, 17% rapid breathing, and 43% rapid heart rate.

No information on the incidence of body ache and

coughing was provided. This variability in symptoms

will make screening more challenging. Based on these

findings, companies are cautioned not to place too

much reliance on only temperature screening. Another

report from a Northern California hospital system indi-

cated that the chief symptoms in 377 adults when pre-

senting in the emergency department were 49%

shortness of breath, 34% fever, and 32% cough (27).

As testing for the SARS-CoV-2 virus to detect infected

individuals and the antibody to detect individuals who

have been infected and recovered becomes widespread,

companies should consider offering testing on a volun-

tary basis as an effective tool for keeping their work-

force. Based on a PDA membership survey (In press)

apparently most employees would accept this offer of

screening. The best method of managing this testing

will become apparent as infectious disease experts gain



more experience managing the pandemic and the sub-

sequent return to work.

Facility and Process Management

Persistence of Coronavirus on Inanimate Surfaces

Human viruses cannot multiply outside of the body and

will not survive on inanimate surfaces for long. An

analysis of 22 studies on the persistence of human

coronaviruses other than SARS-CoV-2 virus (Table I)

reveals that they may persist on metal, glass, or plastic

for up to 9 days (range 2 h to 9 days), but they are read-

ily inactivated within 1 min by disinfectants and spori-

cides such as 62%–71% ethanol, 0.5% hydrogen

peroxide, or 0.1% sodium hypochlorite (28).

The studies summarized in Table I have their technical

limitations as they used related coronaviruses but not

SARS-CoV-2, different types of inoculum prepara-

tions, high inoculum levels, different storage condi-

tions, and reverse transcription polymerase chain

reaction assays as a measure of survival and not infec-

tious units determined by cell culture methods. How-

ever, until additional studies are conducted with the

SARS-CoV-2 virus, these will be indicative and will

contribute to our analysis.

Other agents used in the pharmaceutical industry, includ-

ing the antiseptics 0.05%–0.2% benzalkonium chloride

and 0.02% chlorhexidine digluconate, are less effective,

requiring a contact time of up to 10 min (28). These find-

ings will strictly limit the ability of novel coronaviruses to

contaminate the pharmaceutical supply chain.

A more recent March 17, 2020, letter to the New Eng-

land Journal of Medicine analyzed the aerosol and sur-

face stability of SARS-CoV-2 (COVID-19) and

TABLE I

Persistence of Coronaviruses on Inanimate Surfaces (28)

Type of Surface Virusa

Inoculum (Viral Titer) Persistence (Temperature)

Steel MERS-CoV

HCoV

105

10348 h (20˚C)

8–24 h (30˚C)

5 d (21˚C)

Aluminum HCoV 103 2–8 h (21˚C)

Wood SARS-CoV-1 105 4 d (RT)b

Paper SARS-CoV-1 106

105

104

24 h

3 h

<5min (All at RT)

Glass SARS-CoV-1

HCoV

105

1034 d (RT)

5 d (21˚C)

Plastic SARS-CoV-1

MERS-CoV

SARS-CoV-1

HCoV

105

105

107

105

107

≤5 d (22–25°C)48 h (20°C)6–9 d (RT)4 d (RT)2–6 d (RT)

Polyvinylchloride HCoV 103 5 d (21˚C)

Silicon Rubber HCoV 103 5 d (21˚C)

Surgical Glove (Latex) HCoV 5� 103 ≤5 d (21°C)Disposable Gown SARS-CoV-1 106105104 2 d

24 h

≤8 h (All at RT)Ceramic HCoV 103 5 d (21˚C)

Teflon HCoV 103 5 d (21˚C)aMERS is Middle East Respiratory Syndrome virus; HCoV is Human Coronavirus; SARS-CoV-1 is Severe Acute

Respiratory Syndrome virus.bRT is room temperature.



compared this stability to that of SARS-CoV-1, its

most closely related coronavirus (29). The authors of

the letter reported 10 experimental conditions, con-

ducted in triplicate, involving the two viruses in five

environmental conditions, that is aerosols, inoculated

plastic, stainless steel, copper, and cardboard. SARS-

CoV-2 remained viable as measured by median tissue

culture infectious dose for 50% of the cells to be

infected (TCID50) in the aerosol suspension for the 3 h

duration of the experiment with a reduction in infec-

tious titer from 103.5 to 102.7 TCID50/mL, representing

a half-life of 1.1–1.2 h. In a controlled environment

with many air changes per hour, the virus would be

readily removed from the air.

The coronavirus was more stable on plastic and stain-

less steel than on copper and cardboard. Although the

virus could be detected for up to 72 h, its titer was

greatly reduced (from 103.7 to 100.6 TCID50/mL after

72 h on plastic and from 103.7 to 100.6 TCID50/mL after

48 h on stainless steel). On copper, apparently because

of Cu2+ toxicity, no viable SARS-CoV-2 was measured

after 4 h and on cardboard, no viable SARS-CoV-2 was

measured after 8 h (29). This means, that in the event

that controls established to exclude an infected em-

ployee fail, and in the event that packaged product is

exposed to the virus, the plastic container used for pri-

mary packaging and the cardboard used for secondary

packaging should not carry infectious coronavirus

because of the amount of time the drug products will

be advancing through the supply chain. Therefore,

pharmaceutical products are very unlikely to pose any

risk of infecting pharmacists dispensing, medical staff

administering, and patients taking such products.

The relationship between temperature and relative humid-

ity and the survival of coronaviruses in aerosols and on

surfaces has been investigated. Enveloped viruses were

found to survive longer at lower temperatures and humid-

ity and may persist longer in refrigerators and cold rooms

(30–32). The efficacy of pasteurization (63˚C for 30 min)

was demonstrated with MERS-CoV in camel, goat, and

cow milk with the virus titer reduced from 105.5 to <100.5

TCID50 (33). Clearly, the heat sensitive SARS-CoV-2 vi-

rus will not survive sterilization processes used in sterile

product manufacturing.

Inactivation of Viruses Owing to Routine Cleaning and

Disinfection

The coronavirus may be physically removed from a

surface with a particle-free wipe, inactivated by

detergents in cleaning agents, or inactivated by disin-

fectants and sporicides. In addition to routine cleaning

and sanitization programs established to meet GMP

requirements designed to protect product, companies

should establish cleaning and sanitization of surfaces

in non-GMP areas, including hallways, bathrooms,

offices, and other common areas, to protect the health

and safety of employees during the pandemic. The con-

trols, qualification, and documentation requirements

for GMP activities should be well-established and sub-

ject to change control and/or planned deviation. Such

controls are not required for sanitization programs

designed for the non-GMP areas.

The frequency of cleaning and disinfection of an area

in a GMP manufacturing facility will depend on the in-

tensity of traffic in the area and the exposure of person-

nel to drug product manufacturing. This frequency may

range from weekly, to daily, to before and after each

shift. It should be emphasized that cleaning to remove

grime and product residues prior to the application of

disinfectants is critical for their best efficacy. Table II,

although not exhaustive as the U. S. Environmental

Protection Administration (EPA) List N (34) which

contains 75 agents, provides useful information on rep-

resentative commercially available products, their

active ingredients, contact times, and antiviral claims.

Cleaning and disinfection are considered critical GMP

processing steps especially in sterile product manufac-

turing subject to process validation (see 2004 FDA

Aseptic Processing Guideline). Guidance on the quali-

fication of individual disinfectants and sporicidal

agents may be found in USP <1072> Disinfectants

and Antiseptics (35). Media reports highlight the short-

age of disinfectants and hand sanitizers. Under the cur-

rent circumstance, it is the expert opinion of the

authors that on an interim basis, alternate suppliers

may be identified and a like-for-like substitution made,

forgoing process validation and a vendor audit to make

up for the shortage. Critical elements for making this

like-for-like selection of an alternative source of a dis-

infectant include reputation of the supplier, active in-

gredient, active ingredient concentration, EPA and

other national registration, efficacy claims, whether the

disinfectant formulation is diluted before use or a

ready-for-use product, and sterilization by gamma irra-

diation. To alleviate the shortage of hand sanitizers, the

FDA has authorized the in-house production of alcohol

hand sanitizers (36), but the authors believe that these

materials should not be used in the critical ISO 5 asep-

tic processing areas.



TABLEII

AntivirusActivityofRepresentativeCommonly

UsedDisinfectantsandSporicidalAgentsin

thePharm

aceuticalIndustry

(34)

ActiveIngredient

Product

Name

Company

Contact

Tim

e

(Minutes)

Form

ulation

Type

Emerging

AntiviralClaim

Hydrogen

Peroxide

Accel(Concentrate)

ViroxTechnology

5Dilutable

Yes

Phenolic

LpH

Steris

10

Dilutable

Yes

Phenolic

VespheneIIse

Steris

10

Dilutable

Yes

Sodium

Hypochlorite

CloroxPro

TMCloroxV

R

GermicidalBleach

CloroxProfessional

ProductCo.

5Dilutable

Yes

Isopropylalcohol

DECON-A

HOLWFIVR

Form

ula70%

VeltekAssociates

NA

RTU

No

Hydrogen

Peroxide

andPeraceticAcid

DECON-SPORE200V

RPlus

VeltekAssociates

NA

RTU

No

Quaternary

Ammonium;Ethanol

LysolVR

DisinfectantSpray

ReckittBenckiser

LLC

5RTU

Yes

Hydrogen

Peroxide

Oxy-1

Wipes

VoroxTechnology

0.5

Wipes

Yes

Ethanol

PURELLProfessional

DisinfectantWipes

GOJO

Industries

5Wipes

Yes

Sodium

Hypochlorite

CloroxHealthcareVR

BleachGermicidalWipes

CloroxProfessional

ProductsCo.

3Wipes

Yes



Viral Clearance by HVAC Systems and HEPA Filters in

Clean Rooms

Warehouses, offices, laboratories, and manufacturing

and packaging areas in a pharmaceutical manufacturing

plant will be served by heating, ventilating, and air

conditioning (HVAC) systems to maintain targeted

temperature, humidity, and numbers of air changes

appropriate for each of these areas. In addition, clean

rooms and other controlled areas where sterile drug

products are manufactured are supplied with high-effi-

ciency particulate air (HEPA)-filtered air to meet speci-

fied air cleanliness levels as well as more stringent

requirements for temperature, relative humidity, space

pressurization, and number of air changes per hour to

prevent product contamination.

In general, the level of environmental control, the PPE

worn by clean room operators, and the cleaning and

disinfection program will make it unlikely that the co-

ronavirus will persist in clean rooms and contaminate

sterile drug products (37). This leaves questions around

areas served solely by conventional HVAC systems

without HEPA filtration.

The 2014 American Society of Heating, Refrigerating

and Air-Conditioning Engineers (ASHRAE) Position

Document (38) highlights that some infectious diseases

including those caused by coronaviruses are transmit-

ted through the inhalation of airborne infectious par-

ticles, which can be disseminated through buildings by

pathways that include ventilation systems. This trans-

mission may be reduced using dilution ventilation,

directional airflow, room pressure differentials, source

capture ventilation, air filtration, and ultraviolet germi-

cidal irradiation (UVGI), as well as appropriate clean-

ing and disinfection practices.

The ASHRAE document addresses control strategies

(38). In a practical application, a combination of the

individual interventions will be more effective than a

single intervention in isolation. It is recommended that

a heating and air-conditioning engineer be consulted

on the implementation of these strategies. Pharmaceuti-

cal companies may consider improving particle filtra-

tion for the central air handler, adding upper-room

UVGI units, increasing the outdoor ventilation rates,

and avoiding the use of a lower ventilation rate moti-

vated solely by reduced energy consumption.

Small aerosolized particles,<10 lm, generated by talking,

coughing, or sneezing will be suspended in the air and

transported into the lower respiratory tract during breathing

whereas larger drops, 10–25 lm, will fall through the air

and accumulate on horizontal surfaces (39). Aerosols may

be transported some distance by sideways airflows in non-

classified rooms, whereas vertical laminar airflow with

floor-level exit registers will sweep the air clean in classi-

fied clean rooms. Table III provides information on the

number of air changes per hour.

We believe that pharmaceutical manufacturing con-

ducted in classified areas (ISO 8 to ISO 5) will provide

environmental conditions that will adequately clear vi-

ral particles potentially shed by employees. Nonclassi-

fied areas where non-sterile drug products are

manufactured and all packaging and labeling areas will

need to be assessed for the number of air changes (ven-

tilation rate) to facilitate viral clearance and for their

cleaning and disinfection practices. Based on this risk

assessment, changes may be necessary.

Hand Sanitization

Hand washing and sanitization are an essential compo-

nent of GMP controls designed to protect product. In

addition to these routine controls, additional hand sani-

tization stations should be established in non-GMP

areas to mitigate risk to employees.

TABLE III

Air Velocity and Number of Air Changes per Hour in Clean Rooms (39)

Class of Clean room Airflow Type Average Velocity (Ft./Min.) Air Changes/hr.

ISO 8 (Class 100,000) N/M 1–8 5–48

ISO 7 (class 10,000) N/M 10–15 60–90

ISO 6 (Class 1,000) N/M 25–40 150–240

ISO 5 (Class 100) U/N/M 40–80 240–480

N is Non-unidirectional; M is Mixed Airflow; U is Unidirectional. Note: 10 ft/min equals 3.048m/min.



Personal Protective Equipment

As COVID-19 infected individuals cannot be abso-

lutely excluded from our manufacturing sites, PPE will

become more important. A decision should be made

whether the workplace wearing of face masks would be

mandatory or limited to those activities in which per-

sonnel have direct contact with drug products. Table

IV addresses the appropriate PPE to be worn during

non-sterile and sterile drug product manufacturing.

The efficacy of different grades of face masks in

entrapping COVID-19 viral particles has not been fully

established. The level of exposure to coworkers, proc-

essing equipment, and pharmaceutical drug products

may determine the choice from homemade face masks

to cone masks, to medical face masks to N95 grade

face masks (respirators).

The specifications for different grades of face masks

obtained from commercial supply catalogs may include:

1. Certification Standards: Complies with ASTM

F2299; ISO 9001.2015, and ISO 2859-3 1994; ISO 5

Compatible

2. Bacterial Filtration: >92%, >95%, or >99% @ 1.0

lm particle size retention

3. Reduced Particle Generation: Layers ultrasonically

welded to limit particle shedding

4. Effective Pore Size: 1.0, 0.45, or 0.1 lm

5. Usage: Disposable, single use, or re-usage

6. Sterility: Non-sterile or sterile

FDA Regulation of Face Masks as Medical Devices

The FDA regulates face masks and respirators when

they meet the definition of a device under section 201

(h) of the federal Food, Drug, and Cosmetic Act

(FD&C Act). Generally, face masks fall within this

definition when they are intended for a medical pur-

pose, including for use by health care professionals

(41). These classifications are useful in determining

which devices should be used in a pharmaceutical man-

ufacturing facility.

The FDA defines these devices that may be suitable for

use in a GMP manufacturing facility as follows:

Face Mask—A mask, with or without a face shield,

that covers the user’s nose and mouth and may or may

not meet fluid barrier or filtration efficiency levels.

Surgical Mask—A mask that covers the user’s nose

and mouth and provides a physical barrier to fluids and

particulate materials. The mask meets certain fluid bar-

rier protection standards and Class I or Class II flam-

mability tests.

TABLE IV

Appropriate Personal Protective Equipment for Routine Pharmaceutical Manufacturing (40)

Protective Clothing Non-Sterile ManufacturingAreas Sterile Manufacturing Areas

Plant uniform or plant uniform with

overalls for high-risk product and

environment

Yes Yes

Hair/beard coverings Yes Yes

Safety glasses Yes Yes

Dedicated shoes or shoe coverings Yes Yes

Gloves Yes (if in direct product contact) Yes

Face masks Yes (if in direct product contact) Yes

Enclosed respirators Only if manufacturing high-potency,

toxic drugs or infectious biological

agents

Only if manufacturing high-potency,

toxic drugs or infectious biological

agents

Sterile clean room uniforms

(coveralls), hoods, sleeves, goggles,

face masks, and gloves

No Yes, if in critical aseptic processing

area



N95 Respirator—A disposable half-mask filtering face

piece respirator (FFR) that covers the user’s airway

(nose and mouth) and offers protection from particulate

materials at an N95 filtration efficiency level per 42

CFR 84.181. Such an N95 FFR used in a health care

setting is regulated by the FDA under 21 CFR

878.4040 (FDA product code MSH) and is either a

Class II device that is exempt from premarket notifica-

tion requirements under section 510(k) of the FD&C

Act or is a Class II cleared device.

NIOSH Approved N95 Respirator—An N95 respirator,

approved by National Institute for Occupational Safety

and Health, that meets filtration efficiency level per 42

CFR 84.181.

The following are devices suitable for use in a clinical

setting when medical staff treat COVID-19-infected

patients but not in pharmaceutical manufacturing:

Face Shield—A face shield is a device used to protect

the user’s eyes and face from bodily fluids, liquid splashes,

or potentially infectious materials. Generally, a face shield

is situated at the crown of the head and is constructed with

plastic to cover the user’s eyes and face.

Filtering Face Piece Respirator—A filtering face piece

respirator (FFR) is a device that is a disposable half-

face-piece nonpowered air-purifying particulate respi-

rator intended for use to cover the nose and mouth of

the wearer to help reduce wearer exposure to patho-

genic biological airborne particulates.

Surgical N95 Respirator—A disposable FFR used in a

health care setting that is worn by health care personnel

(HCP) during procedures to protect both the patient

and the HCP from the transfer of microorganisms,

body fluids, and particulate material at an N95 filtration

efficiency level per 42 CFR 84.181. A surgical N95

respirator is regulated by the FDA under 21 CFR

878.4040 (FDA product code MSH) and is either a

Class II device that is exempt from premarket notifica-

tion requirements under section 510(k) of the FD&C

Act or is a Class II cleared device.

Given the CDC recommendation that in addition to

social distancing, face masks should be worn when people

leave their places of residence, pharmaceutical companies

should require employees reporting to work to be wearing

face masks and should supply nonmedical masks to be

worn on company premises until this recommendation is

lifted. These face masks would be replaced at least twice a

day and disposed as potential biohazard waste.

In manufacturing areas where pharmaceutical ingre-

dients, packaging components, intermediates, and fin-

ished products are exposed to workers, the PPE

recommendations found in Table IV would be strictly

followed.

Pharmaceutical companies as high-volume users of

face masks may employ strategies to conserve these

devices when they are in short supply. These include

allowing employees to use homemade cloth face masks

to enter their facilities and continue to wear them in

office areas, allowing the removal of face masks in iso-

lated offices that maintain strict social distancing, and,

when strictly necessary, the reuse of surgical masks af-

ter decontamination. On April 9, 2020, the FDA issued

an Emergency Use Authorization (EUA) for the emer-

gency use of a Steris Corporation vapor-phase hydro-

gen peroxide sterilization system for decontaminating

compatible N95 respirators for reuse by medical per-

sonnel to prevent potential exposure to pathogenic air-

borne particulates when the respirators are in short

supply because of the COVID-19 pandemic. The data

submitted by Steris supported up to 10 sterilizations

and reuse. It was noted that cellulose-based face masks

are incompatible with hydrogen peroxide (42).

Vaccines against the SARS-CoV-2 Virus

The availability of safe and effective vaccines would

help relax employee screening, social distancing prac-

tices, and the use of PPE in non-GMP areas. More than

40 different vaccines are in development globally with

at least two now in Phase I human safety trials as of

April 22, 2020. Vaccine clinical development is a com-

plex process, which requires large clinical trials and

establishing the long-term safety of the vaccine. The

history of vaccine development is replete with exam-

ples of safety signals emerging post approval as a result

of unexpected immunological response post immuniza-

tion, for example, Rotashield and Dengvaxia. Further,

it should be noted that there is no approved vaccine for

SARS-COV-1 and for MERS, outbreaks that occurred

in 2002 and 2012, respectively. Because of the wide-

spread disease, recruiting large number of subjects for

clinical trials is not expected to be a hurdle for

COVID-19 vaccines, but this may change as the pan-

demic recedes. Despite all-out efforts, Dr. Anthony

Fauci, Director of the U.S. National Institute of Allergy



and Infectious Diseases, predicts that the availability of

a vaccine will take a year to a year and a half, at least

(43).

Regulatory Responses

Regulatory Response to the COVID-19 Outbreak

On February 11, 2020, when the WHO formalized the

name of the current outbreak as COVID-19, the FDA

immediately added this official disease on their web-

site. This new FDA Webpage will soon fill up with a

wide range of guidance documents and directives in a

very short time. This COVID-19 outbreak has gener-

ated an unprecedented response from the FDA and

other U.S. regulatory agencies to remove many regula-

tory hurdles that were hindering the Industry response

efforts to monitor and treat this pandemic. These dra-

matic changes from the global compliance norm reflect

the seriousness of this viral threat to our medical sup-

ply industry along with the safety of those who work in

these industries and those who may be patients in need

of these pharmaceutical medical products. Among

these U.S. federal agencies are the FDA, the CDC,

OSHA, and the NIH. Their general contribution to the

mitigation and relief of regulatory formalities will be

briefly described following. In a February 14, 2020,

press release, the FDA announced that “if a potential

shortage or disruption of medical products is identified

by the FDA, we will use all available tools to react

swiftly and mitigate the impact to U.S. patients and

health care professionals”. At this time period, the

FDA press releases were focused on the impact of med-

icine and product coming from China owing to the

COVID-19 outbreak that was occurring in that area of

the world. It is very unlikely at that time that the phar-

maceutical industry or regulators knew how signifi-

cantly the subsequent global pandemic would impact

their routine activities. Subsequently, there has been a

significant list of FDA initiatives to minimize the

shortage of essential medicine within the U. S.

because of active pharmaceutical ingredient (API)

unavailability for the manufacturing of the finished

products (FDA announcement date February 27,

2020). Included in this list are the following guidance

documents and directives and their date of issuance:

1. Critical human drug shortages can be mitigated

with lengthening the expiration dates. (FDA, Febru-

ary 27, 2020).

2. A new policy for certain laboratories that develop

and begin to use validated COVID-19 diagnostics

before the FDA has completed review of their EUA

request (FDA, February 29, 2020).

3. The FDA and Federal Trade Commission (FTC)

issued seven warning letters to companies for sell-

ing fraudulent COVID-19 products. The products

cited in these warning letters are teas, essential oils,

tinctures, and colloidal silver. (FDA, March 9,

2020).

4. Coronavirus (COVID-19) Update: The FDA issues

Guidance for Conducting Clinical Trials. The FDA

is aware that protocol modifications may be

required, and that there may be unavoidable proto-

col deviations owing to COVID-19. This would

eventually include expedited early vaccine trial for

the development of a COVID-19 vaccine (FDA,

March 18, 2020).

5. The FDA and National Institutes of Health

(NIH) have begun a randomized controlled trial

for the treatment of COVID-19 patients with the

investigational antiviral drug Remdesivir; inter-

leukin-6 receptor inhibitors; as well as the

application of convalescent plasma and hyper-

immune globulin, antibody-rich blood products

that are taken from blood donated by people

who recovered from the virus infection (FDA,

March 19, 2020).

6. The FDA provides a guidance document entitled

“Temporary policy for preparation of certain alco-

hol-based hand sanitizer products during the public

health emergency”. (FDA, March 20, 2020).

7. The FDA provides maximum flexibility to import-

ers seeking to bring PPE into the U.S. with minimal

disruptions during the importing process. The

agency provided instructions to manufacturers on

how to inform the U.S. Customs and Border Protec-

tion with specific advisement to expedite regulatory

clearance. (FDA, March 24, 2020).

8. The FDA issues an EUA to allow for the emergency

use in health care settings of certain ventilators, an-

esthesia gas machines modified for use as ventila-

tors, and positive pressure breathing devices

modified for use as ventilators (FDA, March 27,

2020).



9. The FDA establishes a new program to expedite the

development of potentially safe and effective life-

saving treatments. The program is known as the

Coronavirus Treatment Acceleration Program

(CTAP). This public-private approach is cutting red

tape, redeploying FDA staff, and working day and

night to review requests from companies, scientists,

and doctors who are working toward therapies.

(March 31, 2020).

10. The FDA issued a new EUA for non-NIOSH-

approved respirators made in China, which makes

KN95 respirators eligible for authorization if cer-

tain criteria are met. (FDA, April 3, 2020).

The authors of this review applaud the FDA in providing

a more flexible regulatory response to the pandemic.

However, caution should be mentioned as to the tem-

porary nature of these allowable regulatory shortcuts

during this pandemic, and the return to standard prac-

tice should be documented to prevent any regulatory

citations made by health authority inspections as the

urgency of this historic event diminishes over time

European Union Regulatory Expectations during the

COVID-19 Pandemic

As with the FDA in the United States, we are seeing a

strong regulatory response to the COVID-19 pandemic

from other regions of the world (43). For example, the

combined organizations of the European Commission

(EC), Heads of Medicines Agencies (HMA), and the

European Medicines Agency (EMA) have published a

Notice to their Stakeholders. The document is entitled

“Questions and Answers on Regulatory Expectations

for Medicinal Products for Human Use During the

COVID-19 Pandemic” (EU Q&A document, April

2020). We will not discuss the entire Q&A in this

review article, but we will highlight some key

responses that the European Union (EU) expressed in

their handling of deviations in manufacturing and

importation of finished products and API as they relate

to GMP and good documentation practice (GDP) issues

during this pandemic.

Among some of the temporary changes include: (1)

measures should be put in place to ensure the validity

of GMP certificates that support manufacture and

importation of medicinal products into the EU should

be extended to avoid disruptions in the availability of

medicines, with a liberal time extension to sites located

inside the EU; (2) with the difficulty to perform on-site

GDP inspections, the validity of GDP certificates will be

extended until the end of 2021 with no further company

action required; (3) remote batch certification and remote

audits of API manufacturers have been expanded, even for

those EU companies previously disallowed from this pro-

cess; and (4) in case of imports of investigational medici-

nal products from outside of the EU, the companies quality

department should ensure that the quality of the batch is in

accordance with the terms of the clinical trial authorization

and meets EU GMP requirements. The EMA recom-

mended to make this assessment remotely; the companies

need to review documents including batch records, in-pro-

cess test reports, validation status of facilities, the results of

any analyses performed after importation, stability reports,

storage and shipping conditions, and so forth. Most gratify-

ing was the response to the question can quality require-

ments be waived/adapted for medicines intended to be

used for the treatment of COVID-19 patients? The short

answer to this question was “No” but with the EMA offer

that if manufacturers were having difficulties performing

the compliance quality control steps, they were invited to

contact the competent authorities and “to present an

adapted control scheme based on a risk-based approach”.

There was additional information to help navigate the reg-

ulatory hurdles posed by the restrictive travel conditions

during this pandemic, so a review of the entire document

is suggested for those manufacturing and conducting busi-

ness in the EU geographic areas.

Overall Risk Assessment

Risk Analysis Tools

A number of risk analysis tools, including quality risk

management, may be used when assessing risk factors.

Tables S-I to S-VI (see Appendix) show an example of

a hazard analysis and critical control points (HACCP)

program approach (originating in the food industry),

which summarizes the common inputs, identifies the

various risks with ratings from low to high, and sug-

gests common risk mitigations or critical process con-

trol points. Risk assessment of the specific steps in the

supply chain for a representative non-sterile and sterile

drug product, that is, activity, risk level, critical control

point, and mitigation are provided (44).

Steps analyzed included staff recruitment, procurement

of pharmaceutical ingredients and packaging compo-

nents, facility design and operation, cleaning and



disinfection, utilities, manufacturing processes, pack-

aging and labeling, warehousing, shipment, dispensing,

and patient usage.

Drug Shortages

A major responsibility of the pharmaceutical industry and

regulators is to anticipate and meet the changed demands for

drug products driven by patient treatment and disruption to

our supply chain. This statement appeared recently on the

FDA website https://www.fda.gov/drugs/drug-safety-and-

availability/guidance-notifying-fda-permanent-discontinuance-

or-interruption-manufacturing-under-section-506c-fdc.

“Due to the COVID-19 pandemic, FDA has been closely

monitoring the medical product supply chain with the ex-

pectation that it may be impacted by the COVID-19 out-

break, potentially leading to supply disruptions or

shortages of drug and biological products in the U.S. The

guidance, Notifying FDA of a Permanent Discontinuance

or Interruption in Manufacturing Under Section 506C of

the FD&C Act, is intended to help applicants and manu-

facturers provide the agency with timely and informative

notifications about changes in the production of certain

drugs and biological products. In urging the submission of

these notifications, the guidance may assist in our efforts to

prevent or mitigate shortages of such products, including

under circumstances outside of the COVID-19 public

health emergency.”

Many pharmaceutical drug products have the potential

to be in short supply because of increased demand to

treat hospitalized COVID-19 patients. Shifting produc-

tion schedules to meet this increasing demand will help

but may create backorders for other needed drugs. The

disruption to the supply chain because of absenteeism

of production and testing personnel, warehousing and

shipping of packaging components, pharmaceutical

ingredients and finished products, and imposition of

national trade barriers to the free distribution of phar-

maceuticals are all serious concerns.

Shortages have been reported for drugs that are used

to keep patients’ airways open, as well as antibiotics,

antivirals, and sedatives (45–47). In March 2020,

orders for broad-spectrum antibiotics like azithromy-

cin and antivirals like ribavirin have tripled; medi-

cines for sedation and pain management like fentanyl,

midazolam, and propofol have increased by 100%,

70%, and 60%, respectively.

Risk Assessment

The authors believe that as SARS-CoV-2 is a commu-

nicable human respiratory virus, the largest risk to the

supply chain is absenteeism among line employees pre-

venting the manufacture, testing, and distribution of

drug products and not product contamination.

There are gaps in our knowledge of the epidemiology

of the COVID-19 pandemic around identifying at-risk

populations and the role of antibodies in preventing

repeat infection that when filled will help manage our

workforce (48).

The cell culture-based manufacturing processes of bio-

logical medicinal products can, and has in several

instances, been infected by viruses (49). The suscepti-

bility of the currently used manufacturing platforms,

such as cell lines CHO, HT1080, and HEK 293 for the

new SARS-CoV-2 has already been tested though, and

the cell lines were found nonpermissive, that is do not

support viral growth, to this new virus (Kreil, 2020 Per-

sonal Communication). See Table V for a summary of

the lack of capacity of the coronavirus to grow in com-

monly used cell lines.

The detectability of the new SARS-CoV-2 has also

been tested, and the cell line panels used in standard in

vitro adventitious virus testing as required by regula-

tory guidance (ICH Q5A (R1)) were found capable of

revealing virus presence (Kreil, 2020 Personal Com-

munication). As might have been expected from expe-

rience with the earlier SARS-CoV, the Vero cell line

was highly susceptible to infection, which was easily

visible by development of a cytopathic effect (49).

The three main risks for viral contamination in cell cul-

ture for therapeutic production are the cell source,

materials used in cell culture, and exposure of the pro-

cess stream to the operators or environment with viral

clearance, that is, inactivation or removal from the

product, being most important in reducing the risk of

virus contamination of the finished product. The reader

is referred to the Consortium on Adventitious Agent

Contamination in Biomanufacturing (CAACB) study

for more details on risk mitigation (49).

Discussion

The objective of our discussion will primarily focus on

the unique current conditions and problems associated



https://www.fda.gov/drugs/drug-safety-and-availability/guidance-notifying-fda-permanent-discontinuance-or-interruption-manufacturing-under-section-506c-fdc



with the controls to minimize disruption of the pharma-

ceutical supply chain and to highlight other factors that

we may not have had the available information to

include in this review publication. Future data and

experiences will eventually fill in the gaps of our cur-

rent understanding and control of the COVID-19

pandemic.

The 2020 COVID-19 global pandemic meets all the

characteristics of “A Black Swan”, what the best-sell-

ing author Nassim Nicholas Talab defined as an event

with low probability, extreme impact, unforeseen, and

retrospective predictability (51). Dr. Talab, a renowned

Professor of Risk and Decision Science, proposed the

Black Swan theory to explain highly improbable

events, and the bias in decision-making introduced by

past experience and by pockets of knowledge not avail-

able to all decision makers.

Low Probability Events

As per the WHO, in 2016 lower respiratory infections

were the deadliest communicable disease, causing 3

million deaths worldwide, and were the fourth overall

on the top 10 global causes of death (52). As per the

CDC, in 2017 influenza and pneumonia were the lead-

ing cause of communicable disease, causing 55,672

deaths in the U.S., and were the eighth overall on the

top 10 causes of death (53). Although scientists under-

stood the possibility of another novel, highly conta-

gious, and deadly respiratory virus outbreak, past

experience gained in managing SARS-CoV-1, H1N1

influenza, and MERS outbreaks that had limited spread

may have introduced a bias among some scientists, pol-

icy makers, and the public at large in assessing

probability and underestimating the rapid spread of the

COVID-19 outbreak into a pandemic.

Extreme Impact Events

The medical impact of a pandemic has been well stud-

ied by scientists; however, the impact of mitigation

strategies such as social distancing, and the impact of a

global end to transportation and the resulting economic

activity was perhaps not well understood and antici-

pated. As such, the scientific, medical, business, and

legal communities had to scramble to find quick solu-

tions and remedies to both the direct and indirect dele-

terious impact from this pandemic. The essential nature

of the pharmaceutical industry to combat pandemics

and its higher level of knowledge and awareness, regu-

latory requirement to have business continuity plans,

regulatory relief, and GMP controls has resulted in rel-

atively less impact on the manufacturing activities of

pharmaceutical companies as compared to many other

manufacturing and service industries.

Unforeseen Events

The complexity of the supply chain, the increased

demand for PPE, and the inability of essential employ-

ees to commute to work during stay-at-home orders

were unforeseen domino effects. When national cata-

strophes (i.e., tornadoes, hurricanes, forest fires) occur

in certain regions of a country there are generally local,

state, or federal contingency plans in place to mitigate

or coordinate the multiresponse to that effected area.

Pandemics being relatively rare events, and each hav-

ing unique characteristics and speed of spread, can

result in many unanticipated challenges.

TABLE V

Capacity of SARS-CoV-2 to Replicate in Primate and Human Cell Lines

Cell Line Cell Line Origin

SARS-CoV

Replicationa

References

CHO Chinese Hamster Ovary Incompatible (Kreil, 2020 Personal Communication)

HEK293 Human Embryonic Cells Incompatible (Kreil, 2020 Personal Communication)

HT1080 Human fibrosarcoma Incompatible (Kreil, 2020 Personal Communication)

A549 Human Adenocarcinoma Cells Incompatible 50

HUH Human Liver Cells Moderate 50

HEK293T Human Embryonic Cells Moderate 50

VERO African Green Monkey Kidney Cells High 50aIncompatible is no growth, no cytopathic effect (CPE); Moderate is growth but no CPE; High is growth and CPE.



Retrospective Predictability

As the pandemic progresses, it is easy to connect the

dots and conclude that the pandemic was predictable

and that different decisions were required. The fast

spread of a novel virus requires decision-making on

limited information and decisions need to be reeval-

uated as new information becomes available. There

needs to be a deliberate and educated infectious disease

preparedness and response plan built into business con-

tinuity plans for the next inevitable pandemic.

Limited Viral Characterization and Transmission

Factors

One of our knowledge gaps as it relates to this infec-

tious virus is our inability to identify asymptomatic

infected individuals and exclude them from the phar-

maceutical workplace without widespread testing for

the virus and its antibodies. This would be followed by

the problem with a lack of follow-up contact investiga-

tions. Lastly, a more definitive assessment of the effi-

cacy of PPE, especially face masks, against the SARS-

CoV-2 virus is needed.

Current Industry Manufacturing Practices That Are

Low Risk

In general, because of the reduced ability of the lipid-

enveloped virus to survive (but not proliferate) outside

the human body, clean room environmental controls,

cleaning and disinfection programs, and the PPE

employed in the pharmaceutical industry are adequate

to prevent COVID-19 viral contamination of our sterile

products manufactured in GMP-compliant facilities

and do not need to be changed. Our review includes

recent information that the COVID-19 virus does not

grow in the conventional manufacturing cell lines used

for the proliferation and production of biologically

based pharmaceutical products (Kriel, 2020 Personal

Communication)

Risk Mitigation Steps That May Need Reevaluation

Areas that may need a closer risk assessment may be

environmental conditions and controls in non-sterile

product manufacturing rooms and all product labeling

and packaging areas. The engineering and operational

standards of the HVAC systems supplying these work-

spaces should be reviewed and, if necessary, improved.

Parameters that may need to be assessed may include

the number of air changes per hour, cleaning and disin-

fection programs, and the PPE worn in these areas.

Because of the low risk of viral contamination of our

GMP-controlled pharmaceutical equipment and manu-

facturing rooms, no product testing for the presence of

the COVID-19 virus is recommended. Until COVID-

19 is better understood, employees holding staff posi-

tions should work from home. Protocols for the even-

tual integration of the total work force back to

pre-COVID-19 activity need to be written and

reviewed, which should include medical and legal staff

to allow for the gradual and specific viral monitoring

with a cognizant determination for those who are at

highest risk to this virus. The reliability of the medical

platform for making these determinations should be

assessed. For example, the benefit of measurable anti-

body blood titers to the COVID-19 virus may not be a

100% reliable factor for preventing reinfection by this

virus.

Critical Risk Mitigation Steps That Should Be Evaluated

Pharmaceutical companies must aggressively screen

their employees for COVID-19 infection and remove

those infected, in a timely manner, from the workplace.

These actions are necessary to avoid absenteeism

because of continuing infection or reinfection of criti-

cal employees and the general work staff and a loss of

employees to manufacture, test, and distribute essential

drug products. A more definitive list of the risk mitiga-

tion steps recommended by the authors will be pre-

sented in the next section.

Conclusions

The authors, from their point-of-view as microbiolo-

gists, have attempted to review the risks and recom-

mend mitigation steps that pharmaceutical companies,

depending on their circumstances, should consider

implementing in their manufacturing facilities.

The PDA has established a COVID-19 task force with

broader representation of the disciplines within our

membership that expand on areas over and above this

review.

Recommendations

The following risk mitigation steps to minimize the

impact of COVID-19 on the pharmaceutical supply



chain based on the risk classification in Figure 1 are

recommended.

Direct Risks Posed by the COVID-19 Pandemic

Personal Health and Safety

1. To facilitate social distancing, employees able to do

their job from home should be allowed to do so while

employees directly involved in the manufacture, test-

ing, packaging, and distribution of pharmaceutical

product should be screened for potential COVID-19

infection and if suspected to be infected should be

excluded from the workplace.

2. Nonessential visitors should be denied entry to all

manufacturing facilities.

3. Additional hand sanitization stations should be in-

stalled in non-GMP areas.

4. Wearing of face masks by all employees in non-

GMP areas should be considered after careful evalua-

tions of the risks and benefits and would not be gov-

erned by GMP procedures.

5. If a safe and efficacious COVID-19 vaccine is

available, it should be made widely available to

the manufacturing employees of pharmaceutical

companies.

Product Quality

1. Meeting GMP requirements related to PPE and

excluding at risk employees from manufacturing

activities will provide adequate assurance.

2. Testing for the presence of COVID-19 in manufac-

turing facilities and products is not recommended.

3. Pharmaceutical GMPs should be strictly maintained.

4. Determine if mammalian cell lines used for biophar-

maceutical production are not susceptible to the

COVID-19 virus.

5. Pharmaceutical companies are encouraged to

actively monitor recommendations from the U.S.

CDC an FDA, the EMA, and the WHO and make

changes to their policies and procedures as the

COVID-19 pandemic recedes.

GMPManufacturing

1. Environmental controls, the appropriate use of PPE,

and cleaning and disinfectant practices, especially in

warehouses, non-sterile manufacturing areas, and

packaging lines should be reviewed and updated if

necessary.

2. Manufacturing and testing schedules can be adjusted

and additional shifts added to facilitate social dis-

tancing and to ensure essential drug products are not

in short supply.

Availability of Supplies

1. Strategies for conserving face masks and other PPE

should be implemented.

2. Enhance collaboration with suppliers, educating

them about their importance to the pharmaceutical

industry.

Indirect Risks Posed by the COVID-19 Pandemic

Availability of Employees

1. Repurpose employees for critical activities.

2. Supply alternative transportation for employees who

commute to work using public transportation.

Transportation Infrastructure

1. Distribute finished goods using dedicated transporta-

tion in place of common carriers.

Regarding the availability of raw materials, for exam-

ple, drug substances, excipients, solvents, processing

supplies, and packaging materials:

1. Strengthen existing supplier relations.

2. Seek alternative suppliers.

Acknowledgments

The authors wish to thank T. Cosgrove, Esq., and A.

Caruso for their assistance in writing the article, and the

members of the PDA COVID-19 Task Force for their

review and helpful comments.



Disclaimer

The opinions and suggestions made by the authors in

this manuscript do not necessarily reflect the policies

and requirements of their affiliated companies.

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Appendix

HACCP Approach to Risk Assessment

A comprehensive risk assessment of the different parts of the

pharmaceutical supply chain may be found in Tables S-VI–S-

XI. The four columns in each table address the input or activity,

potential risk identification, assigned risk rating (low,

moderate, or high), and existing critical process controls and

recommended risk mitigations. The risk assessment model used

is based on food-based HACCP principles that may be

unfamiliar to some people working in the pharmaceutical

industry (45). These represent the informed opinions of the

authors with an emphasis on the risk assessment process and an

attempt to capture all relevant aspects of the steps in the supply

chain.

TABLE S-I

Risk Assessment—Management of Human Resources during COVID-19 Pandemic

Activity Risk Identification Risk Rating

Risk Mitigation/Critical Process

Controls

Recruitment of new staff Local; Regional;

National; International

Low to Moderate Remote interviews; Limit domestic

and international travel; 14-day

quarantine prior to starting work

Training new hires and

existing employees

Lack of information;

Issues not addressed in

corporate policies and

procedures

Moderate to High GMP compliance; Coronavirus

awareness training;Symptoms

identification

Deployment of

employees

Domestic; International Moderate to High Staff functions conducted from home;

Restrictions on nonessential

domestic and international travel;

deferment of large staff meetings

Management and

Supervision of

Employees

Staff and line functions Moderate to High Illness recognition; Monitoring with

thermal sensors; Universal wearing

of non-medical face masks on the

job

Employee Attendance Employees working sick;

Loss of human

resources; Inability to

commute

Low Flexibility in working hours;Stress

importance of staying home when

ill; Provide sickness benefits; Add

company sponsored transportation

when public transportation is

unavailable



TABLE S-II

Risk Assessment—Management of Manufacturing Materials during COVID-19 Pandemic

Materials Risk Identification

Risk

Rating Risk Mitigation/Critical Process Controls

Pharmaceutical

Excipients

Excipients derived from plant, animal, or

mineral origin; Excipients of synthetic

or semisynthetic origin

Low Supplier awareness of potential COVID-19

risk; Standard duration of transit and hold

times

Drug

Substances

Drug substance of synthetic or

semisynthetic origin

Low Standard duration of transit and hold times

Packaging

Components

Glass vials, stoppers and seals (Sterile

products)

Plastic container, heat induction seals and

caps (non-sterile products)

Low Standard duration of transit and hold times;

automation of component handling;

washing, depyrogenation and sterilization

(sterile products)

Labeling

Materials

Labels and package inserts Low Reduce handling during label identification

and reconciliation

Incoming

Potable Water

Ground or surface water Low Communication with local water authority

TABLE S-III

Risk Assessment—Testing of Incoming Pharmaceutical Ingredients, Packaging Components, Intermediates, and

Finished Products during COVID-19 Pandemic

Materials—

Sampling and

Testing Risk Identification

Risk

Rating Risk Mitigation/Critical Process Controls

Sampling of

incoming

materials

Human intervention; Limited

environmental controls in

warehouses

Moderate Personal protective equipment; sampling

booths; labeling sampled containers

Transportation to

the testing area

Transition through the facility Low Disinfection of the surface of containers,

drums, shrink-wrap, and pallets

Sample testing Personnel handling Low Personal protective equipment; limited

access to testing area; environmental

controls

Sample

disposition

Disposal Low Controlled destruction of samples



TABLE S-IV

Risk Assessment—Management of Plant Utilities during COVID-19 Pandemic

Materials— Plant Utilities Risk Identification Risk Rating

Risk Mitigation/Critical

Process Controls

Pharmaceutical-grade water Incoming potable

water

Low Maintain existing

microbial monitoring

program

Pharmaceutical-grade plant air Distribution lines and

delivery nozzles

Low Assure sanitary design

Compressed gases None Low Maintain existing

microbial monitoring

program

HVAC system Poor temperature,

humidity, and air

exchange;

Recirculation and

lack of segregation

Low to Moderate Reduced recirculation in

more critical areas;

Higher air change rates;

High room ultraviolet

germicidal irradiation

Domestic and clean steam None Low None

Vacuum Discharge Low Review vacuum

discharge

Washing facilities Poor design and

opportunities for

cross-contamination

Low to Moderate Access to detergents, hot

water, and hand

sanitizing agents;

Segregation of clean

and dirty materials

Waste and sewage disposal Poor separation Moderate Backflow elimination;

Segregation of clean

and dirty materials



TABLE S-V

Risk Assessment—Representative Non-Sterile Drug Product (Compressed Tablet) during COVID-19 Pandemic

Manufacturing Process Risk Identification Risk Rating


Controls

Incoming material sampling

and testing

Sampling is an invasive

process

Moderate Sampling booths; Personal

protective equipment (PPE)

Warehousing Limited environmental control Low Improved environmental control

Ingredient weighing Weighing is an invasive

process

Low to

Moderate

Evaluate weighing booths and

PPE

Excipient size reduction Equipment cleaning Low Upgrade COP and CIP

operations

Blending Equipment cleaning Low Upgrade COP and CIP

operations

Granulation— Dry

Granulation—Wet

Equipment cleaning Low Upgrade COP and CIP

operations

Compression Equipment cleaning Low Upgrade COP and CIP

operations

Bulk Tablet Storage None Low None

Packaging and labeling Packaging operations are labor

intensive

Low to

Moderate

Evaluate HVAC Systems;

Automation of component

handling; PPE

Finished goods warehousing Poor environmental control Low Improved environmental control

Shipping Lack of chain of custody Low Dedicated carriers

Clean Out-of-Place (COP) and Clean In-Place (CIP).



TABLE S-VI

Risk Assessment—Representative Sterile Drug Products (Liquid-filled Stoppered Glass Vials) during COVID-19

Pandemic

Manufacturing Process Risk Identification Risk Rating


Controls

Incoming material sampling

and testing

Sampling is an invasive

process in a warehouse

Moderate Sampling booths and personal

protective equipment (PPE)

Warehousing Limited environmental

control

Low Improved environmental control

(IEC)

Ingredient weighing Weighing is a labor-

intensive process

Low to Moderate Evaluate weighing booths and

PPE

Bulk solution preparation Solution preparation is a

potentially invasive

process

Low to Moderate Use of Restricted Access Barrier

Systems (RABS) and isolators

Packaging component

preparation

Component loading and

unloading is a


process

Low Automation of component

handling; Depyrogenation and

sterilization of vials and

stoppers

Sterile filtration and aseptic

filling and Sealing

Aseptic processing is a


process

Low Use of RABS and isolators

Visual inspection Inspection is an invasive

process

Low Handling automation; IEC; PPE

Packaging and labeling Packaging is an invasive

process

Low Handling automation;IEC; PPE



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